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<p>Arsenic trioxide (ATO) induces oxidative stress and apoptotic cell death in cancer cells; however, the underlying mechanisms and its effects on other signaling pathways, particularly in breast cancer, remain inadequately understood. The aryl hydrocarbon receptor (AhR) is expressed in breast cancer cells and linked to disease progression, while Notch signaling enhances migratory properties in these cells. The simultaneous use of the AhR agonist (FICZ), AhR antagonist (CH223191), and Notch antagonist (DAPT) was intended to investigate how the modulation of these pathways affects the response of breast cancer cells (MDA-MB-231 and MCF-7 cell) to ATO. We measured cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and cell migration. Results show that ATO significantly reduces cell viability in a dose- and time-dependent manner, decreasing MMP and increasing ROS levels. Notably, co-exposure to ATO and CH223191 for 24&#xa0;h enhanced cell viability, increased MMP, and diminished ROS compared to ATO alone. Also, the ATO + CH223191 + DAPT combination exhibited higher MMP and lower ROS levels than the ATO + FICZ + DAPT combination, indicating AhR inhibition’s critical role in MMP regulation. Although ATO reduced migration compared to controls, adding DAPT or FICZ significantly increased migration percentages. Interestingly, co-exposure to CH223191 did not exhibit this effect and modulated the migratory effects of DAPT + ATO and FICZ + ATO combinations. In conclusion, these findings suggest that AhR stimulation via FICZ may enhance ATO’s therapeutic effects, while simultaneous exposure to ATO, FICZ, and DAPT may lead to additive effects, reducing MMP and increasing ROS levels.</p>

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Unraveling the Mechanisms of AhR-Notch Interplay in Mediating Arsenic Trioxide Cytotoxicity in MCF-7 and MDA-MB-231 Breast Cancer Cell Lines

  • 期刊论文

  • 发表日期：

    2025年2月24日

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  • Amir Shadboorestan,
  • Darya Baluchi,
  • Omid Safa,
  • Amin Reza Nikpoor,
  • Mahnoosh Mokhtarinejad,
  • Mahmoud Omidi

摘要

Arsenic trioxide (ATO) induces oxidative stress and apoptotic cell death in cancer cells; however, the underlying mechanisms and its effects on other signaling pathways, particularly in breast cancer, remain inadequately understood. The aryl hydrocarbon receptor (AhR) is expressed in breast cancer cells and linked to disease progression, while Notch signaling enhances migratory properties in these cells. The simultaneous use of the AhR agonist (FICZ), AhR antagonist (CH223191), and Notch antagonist (DAPT) was intended to investigate how the modulation of these pathways affects the response of breast cancer cells (MDA-MB-231 and MCF-7 cell) to ATO. We measured cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and cell migration. Results show that ATO significantly reduces cell viability in a dose- and time-dependent manner, decreasing MMP and increasing ROS levels. Notably, co-exposure to ATO and CH223191 for 24 h enhanced cell viability, increased MMP, and diminished ROS compared to ATO alone. Also, the ATO + CH223191 + DAPT combination exhibited higher MMP and lower ROS levels than the ATO + FICZ + DAPT combination, indicating AhR inhibition’s critical role in MMP regulation. Although ATO reduced migration compared to controls, adding DAPT or FICZ significantly increased migration percentages. Interestingly, co-exposure to CH223191 did not exhibit this effect and modulated the migratory effects of DAPT + ATO and FICZ + ATO combinations. In conclusion, these findings suggest that AhR stimulation via FICZ may enhance ATO’s therapeutic effects, while simultaneous exposure to ATO, FICZ, and DAPT may lead to additive effects, reducing MMP and increasing ROS levels.